Trifluoromethylpyrimidine-based inhibitors of proline-rich tyrosine kinase 2 (PYK2): structure-activity relationships and strategies for the elimination of reactive metabolite formation.
The synthesis and SAR for a series of diaminopyrimidines as PYK2 inhibitors are described. Using a combination of library and traditional medicinal chemistry techniques, a FAK-selective chemical series was transformed into compounds possessing good PYK2 potency and 10- to 20-fold selectivity against FAK. Subsequent studies found that the majority of the compounds were positive in a reactive metabolite assay, an indicator for potential toxicological liabilities. Based on the proposed mechanism for bioactivation, as well as a combination of structure-based drug design and traditional medicinal chemistry techniques, a follow-up series of PYK2 inhibitors was identified that maintained PYK2 potency, FAK selectivity and HLM stability, yet were negative in the RM assay.
Walker
Daniel P
DP
Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. daniel.p.walker@pfizer.com
Bi
F Christopher
FC
Kalgutkar
Amit S
AS
Bauman
Jonathan N
JN
Zhao
Sabrina X
SX
Soglia
John R
JR
Aspnes
Gary E
GE
Kung
Daniel W
DW
Klug-McLeod
Jacquelyn
J
Zawistoski
Michael P
MP
McGlynn
Molly A
MA
Oliver
Robert
R
Dunn
Matthew
M
Li
Jian-Cheng
JC
Richter
Daniel T
DT
Cooper
Beth A
BA
Kath
John C
JC
Hulford
Catherine A
CA
Autry
Christopher L
CL
Luzzio
Michael J
MJ
Ung
Ethan J
EJ
Roberts
W Gregory
WG
Bonnette
Peter C
PC
Buckbinder
Leonard
L
Mistry
Anil
A
Griffor
Matthew C
MC
Han
Seungil
S
Guzman-Perez
Angel
A
D000818:Animals; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D015195:Drug Design; D051418:Focal Adhesion Kinase 2 / Q000037:antagonists & inhibitors*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D006801:Humans; D008968:Molecular Conformation; D015394:Molecular Structure; D010024:Osteoporosis / Q000188:drug therapy; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D011743:Pyrimidines; D051418:Focal Adhesion Kinase 2; D051416:Focal Adhesion Protein-Tyrosine Kinases